Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)

Optimizing Cooling Strategies at < 6 Hours of Age for Neonatal Hypoxic-Ischemic Encephalopathy

Sponsors

Lead Sponsor: NICHD Neonatal Research Network

Collaborator: National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Source NICHD Neonatal Research Network
Brief Summary

The Optimizing Cooling trial will compare four whole-body cooling treatments for infants born at 36 weeks gestational age or later with hypoxic-ischemic encephalopathy: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. The objective of this study is to evaluate whether whole-body cooling initiated at less than 6 hours of age and continued for 120 hours and/or a depth at 32.0°C in will reduce death and disability at 18-22 months corrected age.

Detailed Description

Hypoxic-ischemic encephalopathy (HIE) is a rare, but life-threatening condition characterized by brain injury due to asphyxia diagnosed at or shortly after birth. According to the World Health Organization, more than 722,000 children died from birth asphyxia and birth trauma worldwide in 2004. An estimated 50-75 percent of infants with severe (stage 3) HIE will die, with 55 percent of these deaths occurring in the first month. Up to 80 percent of infants who survive stage 3 HIE develop significant long-term disabilities, including intellectual disabilities, epilepsy, and cerebral palsy with hemiplegia, paraplegia, or quadriplegia; 10-20 percent develop moderately serious disabilities; and up to 10 percent are normal.

Previous studies have shown treatment with hypothermia to be an effective therapy for HIE. Currently, infants diagnosed with HIE at less than six hours of age are given whole-body cooling, decreasing their core body temperature to 33.5°C (93.2° Fahrenheit) for a period 72 hours using a cooling blanket. This treatment appears to protect the brain, decreasing the rate of death and disability and improving the chances of survival and neurodevelopmental outcomes at 18 months correct age. But additional trials are needed to help define the most effective cooling strategies.

The Optimizing Cooling trial will examine whether cooling for a longer time period and/or to a lower temperature will improve the chance of survival and neurodevelopmental outcomes at 18-22 months corrected age. Eligible infants with HIE will be placed in one of four cooling groups: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. Infants will be monitored closely and receive the care of the Neonatal Intensive Care Unit (NICU).

Infants enrolled in the study will be placed on a cooling blanket - the same type of blanket children's hospitals use in the NICU, in operating rooms during surgeries, and to cool children with high fevers. Each infant will be cooled according to the study group he or she is assigned to. During cooling, the infant's temperature will be very closely monitored by continuous esophageal (core)temperature readings. This will be done by placing a soft, narrow, flexible plastic tube into the infant's nose and down to just above the stomach. Skin temperatures will also be monitored closely. At the end of the assigned period of cooling, the infant will be slowly re-warmed until a normal core temperature of 36.5 to 37.0°C (97.7 to 98.6°C) is reached.

Infants will be examined at 18-22 months corrected age to assess their neurodevelopmental outcomes.

Secondary Studies include:

A. Using aEEG to 1)predict mortality or moderate to severe disability at 18-22 months in term infants with HIE treated with systemic hypothermia and 2) to record electrical seizure activity to compare rewarming initiated at 72 hours and later rewarming that is initiated at 120 hours.

B. Secondary Study includes determining an association between MRI detectable injury and neurodevelopment at 18-22 months.

Overall Status Terminated
Start Date September 2010
Completion Date March 2016
Primary Completion Date March 2016
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Death or Moderate to Severe Disability Birth to 22 months corrected age
Secondary Outcome
Measure Time Frame
Death Birth to 22 months corrected age
Level of Disability Among Survivors Follow up at 18-22 months corrected age
Withdrawal of Care Birth through hospital discharge, average 22 days.
Clinical Neonatal Seizures Through death, discharge, or transfer
Bayley Cognitive Score Follow up at 18-22 months corrected age
Cerebral Palsy Follow up at 18-22 months corrected age
Level of Disability Among Survivors, by Level of HIE Follow up at 18-22 months corrected age
Visual Impairment Follow up at 18-22 months corrected age
Hearing Impairment Follow up at 18-22 months corrected age
Multiple Disabilities Follow up at 18-22 months corrected age
Multiorgan Dysfunction Until death, discharge, or transfer
Enrollment 364
Condition
Intervention

Intervention Type: Procedure

Intervention Name: Whole-body Cooling

Description: Whole-body cooling using a Blanketrol II or III to reach either a target core temperature of 33.5°C or 32.0°C for a duration of either 72 hours or 120 hours.

Eligibility

Criteria:

Inclusion Criteria:

Eligibility will be determined in a stepped process:

1. All infants with a gestational age ≥ 36 weeks will be screened for study entry if they are admitted to the NICU with a diagnosis of fetal acidosis, perinatal asphyxia, neonatal depression or encephalopathy.

2. Infants will be eligible if:

- They have a pH ≤ 7.0 or a base deficit ≥ 16m mEq/ L on umbilical cord or any postnatal sample within 1 hour of age.

- If, during this interval, they have a pH between 7.01 and 7.15, a base deficit is between 10 and 15.9 mEq/L, or a blood gas is not available, AND they have an acute perinatal event AND either a 10-minute Apgar score ≤ 5 or assisted ventilation initiated at birth and continued for at least 10 minutes.

3. Once these criteria are met, eligible infants will have a standardized neurological examination performed by a certified physician examiner. Infants will be candidates for the study when encephalopathy or seizures are present. For this study, encephalopathy is defined as the presence of 1 or more signs in 3 of the following 6 categories:

- Level of consciousness: lethargy, stupor or coma;

- Spontaneous activity: decreased, absent;

- Posture: distal flexion, decerebrate;

- tone: hypotonia, flaccid or hypertonia, rigid;

- Primitive reflexes: a) suck, weak, absent; b) Moro, incomplete, flaccid;

- Autonomic nervous system: a) pupils: constricted, unequal, skew deviation or non reactive to light; b) heart rate: bradycardia, variable heart rate or c) respiration: periodic breathing, apnea.

Eligible infants from multiple births will be enrolled in the same arm of the study.

Exclusion Criteria:

- Inability to randomize by 6 hours of age

- Major congenital abnormality

- Major chromosomal abnormality (including Trisomy 21),

- Severe growth restriction (≤ 1800gm birth weight),

- Infant is moribund and will not receive any further aggressive treatment,

- Refusal of consent by parent

- Refusal of consent by attending neonatologist

- Infants with a core temperature < 33.5°C for > 1 hour at the time of screening by the research team would not be eligible for the study.

Gender: All

Minimum Age: N/A

Maximum Age: 6 Hours

Healthy Volunteers: No

Overall Official
Location
Facility:
University of Alabama at Birmingham | Birmingham, Alabama, 35233, United States
University of California - Los Angeles | Los Angeles, California, 90025, United States
Stanford University | Palo Alto, California, 94304, United States
Emory University | Atlanta, Georgia, 30303, United States
Indiana University | Indianapolis, Indiana, 46202, United States
University of Iowa | Iowa City, Iowa, 52242, United States
Wayne State University | Detroit, Michigan, 48201, United States
Children's Mercy Hospital | Kansas City, Missouri, 64108, United States
University of New Mexico | Albuquerque, New Mexico, 87131, United States
University of Rochester | Rochester, New York, 14642, United States
RTI International | Durham, North Carolina, 27705, United States
Duke University | Durham, North Carolina, 27710, United States
Cincinnati Children's Medical Center | Cincinnati, Ohio, 45267, United States
Case Western Reserve University, Rainbow Babies and Children's Hospital | Cleveland, Ohio, 44106, United States
Research Institute at Nationwide Children's Hospital | Columbus, Ohio, 43205, United States
Univeristy of Pennsylvania | Philadelphia, Pennsylvania, 19104, United States
Brown University, Women & Infants Hospital of Rhode Island | Providence, Rhode Island, 02905, United States
University of Texas Southwestern Medical Center at Dallas | Dallas, Texas, 75235, United States
University of Texas Health Science Center at Houston | Houston, Texas, 77030, United States
Location Countries

United States

Verification Date

March 2019

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 4
Arm Group

Label: 33.5°C for 72 hours

Type: Active Comparator

Description: Target Temp: 33.5°C Duration: 72 hrs

Label: 33.5°C for 120 hours

Type: Experimental

Description: Target Temp: 33.5°C Duration: 120 hrs

Label: 32.0°C for 72 hours

Type: Experimental

Description: Target Temp: 32.0°C Duration: 72 hrs

Label: 32.0°C for 120 hours

Type: Experimental

Description: Target Temp: 32.0°C Duration:120 hrs

Study Design Info

Allocation: Randomized

Intervention Model: Factorial Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov